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Resistance Presentations at ICAAC

Written by Mark A. Wainberg, Ph.D.
Published on HIVresistanceWeb: March 4, 2002

The 41st Annual ICAAC took place in Chicago between December 15-19, 2001, and included a number of important presentations on the topic of HIV drug resistance. While most of this work was presented in the form of posters, several oral presentations also dealt with this topic.

1. Technical aspects of resistance testing
2. Population studies
3. Nucleosides and nucleotides
4. NNRTIs
5. Protease inhibitors
6. Fusion inhibitors
References

1. Technical aspects of resistance testing
From a technical standpoint, several of the presentations dealt with comparisons among different techniques for genotyping. As an example, abstract I-1744 by Huang et al dealt with a comparative study by HIV-1 genotyping groups using samples from pediatric patients in ACTG trials [1]. In this study, electronic samples were sent to a variety of laboratories for evaluation, following appropriate editing of the information sent. In spite of the fact that the laboratories that participated in the study varied in terms of the editing strategy that they employed, a high degree of agreement was obtained with respect to actual sequences. Nonetheless, this study highlights the need for appropriate guidelines for editing as employed in genotyping strategies.

A second abstract (I-1745) by Been-Tiktak et al presented information on the use of the RetroGram interpretative program [2]. The results demonstrated a high level of correlation between results obtained by phenotyping versus genotypic interpretation by the RetroGram, which applies an algorithm-based interpretative system to clinical data. These authors agreed that expert interpretation of algorithms was an important process in evaluation of resistance and that this subject required further validation.

2. Population studies
A study by C. Tural et al (I-1746) followed a subset of 60 heavily drug experienced patients who had been randomized into the non-genotyping arm of the Havana trial [3]. These samples were analyzed retrospectively using the RetroGram system and retrospective analysis demonstrated that a software genotyping score (SGS) was capable of predicting virologic response in these individuals. This involves the assignment of scores with respect to susceptibility or resistance for each antiretroviral drug, based on interpretation of genotypic analysis.

In abstract I-1747, Balaguera et al discussed virologic responses to antiretroviral therapy in chronically infected, drug-naive individuals who showed resistance-associated mutations at baseline [4]. Consistent with findings from other groups, this study reported that resistance-associated mutations at baseline were present in 18% of these individuals. Although virologic failure was not seen in any of the 88 patients who were followed, the time to achieve undetectable levels of viral RNA appeared to be longer in those who did possess such mutations than in those who did not. This study points to a need to assess the benefits of genotypic testing in all antiretroviral therapy-naive patients as a guide to initial treatment strategy.

In abstract I-1748, Paxinos et al presented information on the PhenoSense assay and showed that this method is capable of monitoring resistance involving a broad spectrum of HIV-1 subtypes [5]. In abstract I-1749, Vingerhoets et al demonstrated that HIV RNA could be isolated from gastrointestinal mucosal tissue, and that sequences derived from this material yielded similar mutations in RT and protease as did plasma-derived HIV [6]. Similar information was presented with respect to phenotyping.

On the topic of resistance mutations in primary infection and in naive patients, Guerrero et al (abstract I-1753) demonstrated that relatively low rates of resistance-associated mutations were present in subjects in Spain between 1997-2001, as measured by phenotypic assay [7]. In contrast, more than half of the subjects tested appeared to have at least one primary resistance-associated mutation when genotype analysis was conducted.

Studies were also reported on the prevalence of mutations in individuals with treatment failure. In one study (abstract I-1750), Lee and Griswold showed that patients experiencing low-level treatment failure (<400 copies of RNA/mL) had a relatively high prevalence of mutations associated with certain antiretroviral drugs but not others, depending on the treatment regimens that had been employed [8]. They argued that ultrasensitive genotyping procedures will ultimately be needed for optimal clinical management. Abstract I-1751 dealt with virologic and immunologic characteristics of patients showing discordant responses to HAART. This group demonstrated that the presence of resistance-related genotypic mutations was higher in patients with discordant responses to HAART than in patients undergoing HAART failure. In abstract I-1752, Maggiolo et al studied the issue of drug recycling and salvage therapy [9]. They observed that M184V appeared to be unique in that it was the only mutation that tended to be cleared rapidly once patients ceased to take drugs that select for the substitution.

3. Nucleosides and nucleotides
The subject of tenofovir was studied in abstract I-1754 by Tuske et al who studied a template-primer containing a thiol-G that was covalently linked to HIV RT that was blocked at the 3' terminus by tenofovir [10]. Crystal structure analysis revealed that the acyclic nature of tenofovir helps to explain its favorable resistance profile and activity. Furthermore, excision of tenofovir from tenofovir-terminated primers may be less likely to occur, as compared with excision involving other chain terminators. Abstract I-1755 (Naeger et al) also dealt with the subject of nucleoside removal and drug resistance [11]. Chain terminator removal was confirmed for each of AZT, d4T, and ddC in the presence of ATP. However, only intermediate levels of removal were reported with ABC and DXG and, in contrast, each of tenofovir, ddI and 3TC showed only minimal levels of removal under these conditions. They hypothesized that the inefficient removal of tenofovir may contribute to the durable antiviral activity of this drug and its favorable resistance profile. In abstract I-1756, Harrigan et al examined almost 5,000 HIV samples from treatment-experienced patients [12]. They reported that reduced susceptibility to tenofovir was relatively infrequent and that tenofovir had potential in salvage therapy.

The subject of abacavir resistance was studied in abstract I-1758 by Fenner et al [13]. This group reported that the V118I mutation in RT can mediate resistance to ABC in the absence of M184V. The M41L mutation may have augmented this effect. The data suggest that AZT/3TC usage may result in cross-resistance to abacavir. In abstract I-1759, Shulman et al examined the impact of the M184V mutation on HIV phenotypic resistance to nucleoside analogues in drug experienced patients [14]. This group found that M184V/I was associated with decreased phenotypic resistance to AZT and d4T in the presence of thymidine-associated mutations (TAMs).

In contrast, the presence of 184V and TAMs resulted in increased resistance to both ddI and ABC. In abstract I-1760, Pellegrin showed that resistance mutations were frequently observed in the DNA of PBMCs in patients with long-term plasma viral suppression [15]. This group found that virologic outcome was related to the number of prior drugs used in treatment but not to the presence of TAMs in PBMC DNA at baseline. These findings suggest that viral release may be derived from sanctuaries other than plasma and that resistance-associated mutations had been archived at these sites. In presentation I-1761, Lanier et al discussed the ZORRO trial and showed that sensitivity to ABC could be retained despite patients having a median of 4 nucleoside-associated mutations [16].

Abstract I-1324 by Larder et al dealt with genetic determinants of resistance to ddI [17]. In this context, a resistance database consisting of 7,196 recent isolates, for which both genotypes and phenotypes were available, was analyzed. This group concluded that phenotypic resistance to ddI occurred less frequently than that in regard to other nucleosides, i.e., AZT, 3TC, ABC. However, modest resistance to ddI could be explained by a combination of mutations at positions 118I and 69D, as well as 74V, acting in concert with mutations associated with resistance to AZT. In contrast, 184V did not appear to play a significant role in regard to ddI resistance. High-level resistance to ddI could also be attributed to the 151M complex.

4. NNRTIs
The subject of resistance to NNRTIs was also addressed in several presentations. In abstract I-1762, Kemp et al showed that the Y318F mutation can confer high level resistance to NNRTI in clinical samples [18]. Y318F could also act in concert with other known NNRTI mutations to further augment levels of resistance to these compounds. In abstract I-1763, Zaccarelli et al demonstrated the likelihood of cross-resistance to efavirenz in patients having undergone treatment failure with nevirapine [19].

5. Protease inhibitors
The topic of resistance to protease inhibitors was examined in a number of studies. In abstract I-1764, Zolopa et al demonstrated that patients harboring mutations in PR at positions 82 and 90 often failed to respond to SQV/r despite the absence of high level resistance to SQV [20]. They suggested that higher doses of SQV may be preferable in patients who fall into this category.

Abstract I-1765 by Macguire et al demonstrated that mutations in Gag p6 protein can be responsible for phenotypic resistance to PI and that mutations in p6 can also contribute to increased fitness of I50V PI-resistant variants [21]. They concluded that since I50V is a mutation associated with resistance to amprenavir (APV), that these data provide evidence for a high genetic barrier to amprenavir resistance in the clinical setting. This topic was also addressed in abstract I-1766 by Harris et al who argued that selection of a specific APV-resistant genotype is a balance between viral fitness and levels of resistance reported in clinical samples [22]. In this context, the APV-specific mutation I50V is associated with both diminished susceptibility to this drug as well as diminished viral fitness.

Abstract I-1767 by Furfine et al provided x-ray crystallographic data to explain cross-resistance among protease inhibitors [23]. In this context, the I50V mutation is known to confer significant resistance to APV and only minimal cross-resistance to both nelfinavir and indinavir. This is apparently due to the fact that APV has a condensed conformation and cannot easily collapse into the I50V protease structure.

Resistance to lopinavir/r was also examined in a number of studies. In abstract I-1768, Bernstein et al showed that the incidence of resistance mutations may be significantly lower in patients who receive lopinavir/r as opposed to nelfinavir and who have viral loads higher than 400 copies/mL [24]. In abstract I-1769, Harrigan et al demonstrated that samples resistant to several PI (particularly indinavir and ritonavir) may, in general, demonstrate diminished sensitivity to lopinavir/r [25]. Abstract I-1770 by Larder et al showed that resistance to lopinavir/r can be predicted by a series of 28 mutations in the HIV-1 PR gene and that neural networks can be used to quantity levels of such resistance based on genotype [26].

6. Fusion inhibitors
In abstract I-1771, the topic of fusion inhibitors was addressed by Caumont et al who studied polymorphisms within the HIV gp41 protein [27]. This group concluded that resistance to fusion inhibitors such as T-20 may be conferred by regions of gp41 not thought to be directly involved with the fusion process and that this subject requires further evaluation.

In presentation I-669 Miralles et al presented confirmatory data that the fusion inhibitor T-1249 was able to achieve dose-related suppression of plasma viral RNA in individuals possessing multiple resistance mutations associated with each of the NRTI, NNRTI, and PI [28].


References
(NOTE: hotlinks to abstracts may require registration for Abstracts Online)

  1. D. HUANG, D. BRAMBILLA, S. ESHLEMAN, P. PALUMBO, J. BREMER. Evaluation of the Editing Process in HIV-1 Genotyping Assays (for the Pediatric ACTG Sequencing Working Group). 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1744.
  2. A.M BEEN-TIKTAK, K. KORN, W. KEULEN, E. SCHWINGEL, H. WALTER, B. SCHMIDT, H. STIRNADEL, J. SCHAPIRO, C. BOUCHER. Evaluation of an Open Expert-Based Genotype Interpretation Program: RetroGram. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1745.
  3. C. TURAL, L. RUIZ, CH BOUCHER, G. SIRERA, E. NEGREDO, A. BONJOCH, N. CERDÀ, A. JOU, J. ROMEU, A. BALLESTEROS, C. REY-JOLY, B. CLOTET. A Software Genotyping Score (SGS) Predicts Virologic Response in HIV+ Heavily Drug Experienced (HDE) Patients in Clinical Setting. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1746.
  4. H. U. BALAGUERA, G. HANNA, T. HEEREN, K. STEGER, K. FREEDBERG, R. D'AQUILA, D. CRAVEN. Virologic Response to Antiretroviral Therapy in Chronically HIV-1-Infected, Antiretroviral-Naïve Adults with Baseline Genotypic Resistance. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1747.
  5. E. E. PAXINOS, H. WERHANE, M. T. WRIN, J. M. WHITCOMB, C. J. PETROPOULOS. Measurement of Drug Susceptibility and Replication Capacity of Six Different HIV-1 Subtypes: A, B, C, D, F, and G. ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1748.
  6. J. VINGERHOETS, M. A. POLES, J. ELLIOTT, R. HARRIGAN, B. LARDER, P. MCKENNA, K. HERTOGS, P. A. ANTON. HIV RNA from Gastrointestinal Mucosa Shows Similar RT and Protease Mutations and Phenotypic HIV-1 Drug Resistance as Plasma-derived HIV. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1747.
  7. ANTONIO GUERRERO, ANGELINA CAÑIZARES, DAVID VELASCO, MONICA CARTELLE, CONCEPCIÓN GIMENO, JUAN GARCIA DE LOMAS, ON BEHALF OF THE STUDY GROUP FOR PRIMARY RESISTANCE OF HIV IN SPAIN. Resistance Rate of HIV in Naive Patients during the Last 4 Years in Spain. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1753.
  8. SHING-YI D. LEE, MARSHALL GRISWOLD. Prevalence of PR/RT Mutations in Patients with Low-Level Treatment Failure. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1750.
  9. F. MAGGIOLO, A. CALLEGARO, G. GREGIS, G. QUINZAN, C. ARICI, D. RIPAMONTI, R. ROTA, A. GOGLIO, F. SUTER. Drug Recycling in Salvage Therapy. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1752.
  10. S. TUSKE, S. SARAFIANOS, A. D. CLARK, JR., J. DING, L. K. NAEGER, M. D. MILLER, C. S. GIBBS, D. M. JERINA, S. HUGHES, E. ARNOLD. Structure of a Complex of HIV-1 RT with dsDNA Template-Primer Terminated with Tenofovir. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1754.
  11. L. K. NAEGER, K. L. WHITE, N. MARGOT, S. TUSKE, S. SARAFIANOS, E. ARNOLD, M. MILLER. Nucleoside RT Inhibitor Removal and Nucleoside RT Resistance. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1755.
  12. P. R. HARRIGAN, P. MCKENNA, B. A. LARDER, M. D. MILLER. Phenotypic Analysis of Tenofovir Susceptibility among 5000 Clinical HIV-1 Isolates. xxx
  13. THOMAS E. O. FENNER, N. WIESE, H. MUELLER, U. SCHMITZ, H. PETERSEN. M184V Independent Resistance to Abacavir Detected by HIV Phenotypic Assay. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1758.
  14. N. SHULMAN, R. BOSCH, N. WANG, M. ALBRECHT, N. HELLMANN, D. KATZENSTEIN. Impact of M184V/I Mutation on HIV Phenotypic Resistance to Nucleoside Analogs (nRTIs) in nRTI-Experienced Patients. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1759.
  15. ISABELLE PELLEGRIN. Simplified Abacavir (ABC)-Based Triple NRTI Regimens in Patients with Long-Term Plasma Viral Suppression on Protease Inhibitor-Based Regimen: Relevance of Proviral DNA HIV Genotype. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1760.
  16. E. R. LANIER, M. KUBOTA, L. YAU, S. HESSENTHALER, J. HERNANDEZ. Diverse Effects of NRTI-Associated Mutations on Resistance to Abacavir, Stavudine and Zidovudine in the ZORRO Trial. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1761.
  17. B. A. LARDER, S. BLOOR. Analysis of Clinical Isolates and Site-Directed Mutants Reveals the Genetic Determinants of ddI Resistance. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1324.
  18. S. KEMP, M. SALIM, D. STAMMERS, B. WYNHOVEN, B. LARDER, P. R. HARRIGAN. A Mutation in HIV-1 RT at Codon 318 (Y to F) Confers High Level NNRTI Resistance in Clinical Samples. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1762.
  19. M. ZACCARELLI, A. CINGOLANI, C. GORI, M.G. RIZZO, M.P. TROTTA, S. DI GIAMBENEDETTO, E. GIRARDI, A. DE LUCA, C.F. PERNO, A. ANTINORI. Cross-Resistance among Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Limits Recycling Efavirenz (EFV) after Nevirapine (NVP) Failure. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1763.
  20. A. R. ZOLOPA, M. GONZALES, H. RICE, K. HERTOGS, R. SHAFER. Protease Inhibitor Experienced Patients with Protease Mutations 82A and 90M: Saquinavir Phenotype (PT) and Response to Saquinavir/Ritonavir (SQV/RTV). 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1764.
  21. MICHAEL F. MAGUIRE, S. MACMANUS, P. GRIFFIN, C. GUINEA, W. HARRIS, N. RICHARDS, J. WOLFRAM, M. TISDALE, W. SNOWDEN, J. P. KLEIM. Variations in HIV-1 Gag p6 Contribute to the Amprenavir-Specific Protease I50V Resistance Pathway. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1765.
  22. W. HARRIS, S. RANDALL, V. MANOHITHARAJAH, F. XU, R. ELSTON, M. TISDALE, W. SNOWDEN. Impact on Fitness Conferred by Amprenavir (APV) Resistance Mutations. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1766.
  23. Furfine et al. Reference information not available. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-17677.
  24. B. BERNSTEIN, D. KEMPF, M. KING, J. MOSELEY, K. GU, P. CERNOHOUS, E. BAUER, E. SUN. Comparison of the Emergence of Resistance in a Blinded Phase III Study with Kaletra (Lopinavir/Ritonavir) or Nelfinavir Plus d4T/3TC from Week 24 through 96. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1768.
  25. P. R. HARRIGAN, C. VAN DEN EYNDE, B. A. LARDER. Quantitation of Lopinavir Resistance and Cross-Resistance and Phenotypic Contribution of Mutations Shared with Other Protease Inhibitors. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1769.
  26. B. LARDER, D. WANG, R. HARRIGAN. A 28-Mutation Neural Network Model that Accurately Predicts Phenotypic Resistance to Lopinavir (LPV). 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1770.
  27. ANNE CAUMONT, I. GARRIGUE, J. L. PELLEGRIN, H. FLEURY, I. PELLEGRIN. Polymorphism of HIV-1 gp 41 Protein in Naive and Highly Active Antiretroviral Therapy (HAART) Experienced Patients. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-1771.
  28. G. DIEGO MIRALLES, R. DEMASI, P. SISTA, T. MELBY, F. DUFF, T. MATTHEWS. Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors and Antiretroviral History Do Not Affect Virologic Response To T-1249. 41st ICAAC. 16-29 Dec 2001, Chicago, USA. Abstract I-669.



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